No description available

Dopamine (DA) is essential for the production of vigorous actions, but how DA modifies the gain of motor commands remains unclear. Here we show that subsecond DA transients in the striatum of mice are neither required nor sufficient for specifying the vigor of ongoing forelimb movements. Our findings have important implications for our understanding of how DA contributes to motor control under physiological conditions and in Parkinson’s disease. Liu and colleagues show that the vigor (that is, speed and amplitude) of dexterous movements is not controlled by ongoing fluctuations in extracellular dopamine within the dorsal striatum of mice.

Base editing is a CRISPR-based technology that enables high-throughput, nucleotide-level functional interrogation of the genome that is essential for understanding the genetic basis of human disease and informing therapeutic development. Base editing screens have emerged as a powerful experimental approach, yet significant cell-to-cell variability in editing efficiency introduces noise that may obscure meaningful results. Here we develop a co-selection method that enriches for cells with high base editing activity, substantially increasing editing efficiency at a target locus. We evaluate this activity-based selection method against a traditional screening approach by tiling guide RNAs across TP53, demonstrating its enhanced capacity to pinpoint specific mutations and protein regions of functional importance. We anticipate that this modular selection method will enhance the resolution of base editing screens across many applications. This study presents a splice-based selection method

No description available

No description available

Optogenetics has transformed basic research on neural circuitry, led to diverse experimental insights into human brain function and dysfunction, and opened pathways for clinical translation based on new understanding of how specific cell types contribute to cognition and behavior. Many of these translational pathways do not rely on the direct application of optogenetics in humans, but rather develop and advance other treatment modalities by leveraging causal knowledge derived from optogenetic circuit neuroscience. However, a recent proof-of-principle study—showing that optogenetics applied directly to the human central nervous system can treat blindness—underscores not only the curative potential but also the need for careful ethical consideration in the extension of direct optogenetic intervention to other disorders. Here, we review relevant considerations—including the selection of clinical indications, identification of molecular and optical strategies for specificity, and navigatio

No description available

No description available

When and how motor cortical output directly influences limb muscle activity through descending projections remain poorly resolved, impeding a mechanistic understanding of motor control. Here we addressed this in mice performing an ethologically inspired climbing behavior. We quantified the direct influence of forelimb primary motor cortex (caudal forelimb area) on muscles across the muscle activity states expressed during climbing. We found that the caudal forelimb area instructs muscle activity pattern by selectively activating certain muscles, while less frequently activating or suppressing their antagonists. From Neuropixels recordings, we identified linear combinations (components) of motor cortical activity that covary with these effects. These components differ partially from those that covary with muscle activity and differ almost completely from those that covary with kinematics. Collectively, our results reveal an instructive direct motor cortical influence on limb muscles tha

No description available

No description available

Structure-based sequence redesign or inverse folding can significantly enhance structural stability but often compromises functional activity when performed using existing models. Here, we introduce ABACUS-T, a multimodal inverse folding model that improves precision and minimizes functional loss. ABACUS-T unifies several important features into one framework: detailed atomic sidechains and ligand interactions, a pre-trained protein language model, multiple backbone conformational states, and evolutionary information from multiple sequence alignment (MSA). Redesigned proteins show notable improvements: an allose binding protein achieves 17-fold higher affinity while retaining conformational change; redesigned endo-1,4-β-xylanase and TEM β-lactamase maintain or surpass wild-type activity; and OXA β-lactamase gains altered substrate selectivity. All achieve substantially increase thermostability (∆Tm ≥ 10 °C). In each test case, these enhancements are achieved by testing only a few seque

No description available

No description available

Type 2 diabetes is an established risk factor for dementia. However, how its genetic heterogeneity affects different dementia subtypes remains unclear. In this study, we investigate the associations between genetic risk of type 2 diabetes and dementia subtypes among 33,136 older Chinese adults from the KARE cohort. We find that a higher overall polygenic risk score for type 2 diabetes is significantly associated with an increased risk of vascular dementia, but not Alzheimer’s disease. Further analyses using cluster-specific partitioned polygenic score show that elevated genetic risk specific to the hyperinsulinemia pathway is strongly associated with increased incidence of vascular dementia. These findings highlight the potential role of insulin-related metabolic abnormalities in the pathogenesis of vascular dementia and provide genetic evidence to support the use of the hyperinsulinaemia pathway as a clinically relevant marker for early risk stratification and precision prevention str

No description available

No description available

Emerging evidence suggests a correlation between CD8+ T cell–tumour cell proximity and anti-tumour immune response1,2. However, it remains unclear whether these cells exist as functional clusters that can be isolated from clinical samples. Here, using conventional and imaging flow cytometry, we show that from 21 out of 21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumour cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing analysis revealed that T cells from clusters were enriched for gene signatures associated with tumour reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, whereas TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than when conjugated to tumour cells. T cells that were expanded from clusters ex vivo exerted on average ninefold increased killing activity towards autologous melanomas, which

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs), a transient cell stage during myelination that is often stalled at human demyelinating lesions. PreOLs extend processes, surveying nearby axons to begin ensheathment. The lack of genetic tools to visualize and manipulate preOLs has hindered their in-depth study. Here we present a CreERT2 knockin mouse line that enables genetic labeling, lineage tracing, manipulation and multimodal profiling of preOL subsets across the central nervous system. Genetically labeled preOLs are postmitotic, with distinct morphology and unique transcriptomic, epigenetic and electrophysiological features. PreOL lineage tracing revealed spatiotemporal dynamics of oligodendrogenesis across the mouse brain. Moreover, fate mapping of preOLs under sensory deprivation revealed that neuronal activity influences preOLs within a narrow maturation window, promoting their survival

No description available

No description available

The blood–brain barrier (BBB) performs intricate and dynamic functions that extend far beyond its traditional role as a static protective barrier, playing a pivotal role in maintaining CNS homeostasis. These multifaceted functions are rooted in its specialized architectural and cellular composition. In this Review, we examine the dynamic modulation of BBB function during physiological conditions and the hypothesis that such modulation contributes directly to neural and glial plasticity. We provide an integrated examination of the BBB’s diverse cellular components — endothelial cells, pericytes, astrocytes, microglia and vascular smooth muscle cells — across different CNS vascular segments. We discuss how physiological features and states, including circadian rhythms, physical activity, stress and hormonal fluctuations, dynamically alter BBB permeability and signalling, potentially shaping synaptic function, neuronal circuit dynamics and glial responsiveness. Understanding these mechani

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component1. It affects around 5% of children and 2.5% of adults2, and is associated with several severe outcomes3–11. Common genetic variants associated with the disorder have been identified12,13, but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A, ANO8 and ANK2; P < 3.07 × 10−6; odds ratios 5.55–15.13) that are implicated in ADHD. The protein–protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neur

No description available